In a principal aspect the present invention comprises apparatus and preparation methods, by a spray drying technique for forming nanostructured particles of bioactive materials that have high reactivity, small particle sizes and high surface areas. Such manufactured materials have performance advantages in a range of biomedical applications.
The mineral component of bone and teeth consists primarily of non-stoichiometric and highly substituted hydroxyapatite (HA) in poorly crystalline or nearly amorphous forms. The “impurity” components that are present at significant levels in such biominerals include sodium, potassium, magnesium, and strontium substituting for calcium, carbonate for phosphate, and chloride and fluoride for hydroxyl ions. Because HA is stable under in vivo conditions and is osteoconductive, synthetic HA has been widely used in hard tissue repair application, such as implant coatings and bone substitutes. Other calcium phosphate phases have also been shown to be highly biocompatible and/or osteoconductive. As a result, with the exception of fluorapatite (FA), the calcium phosphate compounds listed in Table 1 have been used in some form of bone repair applications.
TABLE 1Calcium Phosphate Compounds thatHave Being Used in Bone Repair ApplicationsCompoundFormulaBone repair applicationsMonocalciumCa(H2PO4)2H2OComponents of calciumphosphatephosphate cement (CPC)monohydrate[Mejdoubi et al., 1994](MCPM)DicalciumCaHPO4CPC component [Brown andphosphateChow, 1987]anhydrous(DCPA)DicalciumCaHOP42H2OCPC product [Bohner et al.,phosphate1995]dehydrateCPC component [Brown and(DCPD)Chow, 1987]OctacalciumCa8H2(PO4)65H2OCPC product [Bermudez et al.,phosphate1994](OCP)α-Tricalciumα-Ca3(PO4)2CPC component [Ginebra et al.phosphate1997](α-TCP)β-Tricalciumβ-Ca3(PO4)2CPC component [Mejdoubi et al.,phosphate1994](β-TCP)Granular bone graft [Ogose et al.,2002]AmorphousCa3(PO4)2CPC component [Lee et al., 1999]calciumphosphate(ACP)HydroxyapatiteCa5(PO4)3OHCPC product [Brown and(HA)Chow, 1987]; granular bonegraft [den Boer et al., 2003];Implant coating [Jaffe and Scott,1996]FluorapatiteCa5(PO4)3F(FA)TetracalciumCa4(PO4)2OCPC component [Brown andphosphateChow, 1987](TTCP)
Calcium phosphate compounds are also useful in various dental applications. For example, a slurry or gel that contained MCPM and fluoride was used as topical F agents that produced significant amounts of both tooth-bound and loosely bound F deposition on enamel surfaces. A chewing gum that contained α-TCP as an additive released sufficient amounts of calcium and phosphate ions into the oral cavity and significantly alleviated cariogenic challenges produced by sucrose. A calcium phosphate cement that contained TTCP and DCPA was shown to provide effective apical seal when used as a root canal filler/seal, or as a sealer with as a retrievable master cone. The cement was also effective as a perforation sealer. ACP or a TTCP+DCPA mixture has been used as the mineral source in remineralizing dental restorative materials.
In addition to calcium phosphates, a number of calcium-containing compounds also have significant dental applications. Calcium fluoride, CaF2, which is the major product of most topically applied F (F dentifrices, F rinses, professionally applied F gel, etc.), is the source of ambient F in the mouth that is primarily responsible for the cariostatic effects of F. The greater the amount of CaF2 that adheres to the oral tissue surfaces after a F application, the greater is the oral F retention and therefore the F cariostatic effects. Calcium-silicate compounds, tricalcium silicate and dicalcium silicate, are the major components of mineral trioxide aggregates (MTA), a material that finds wide uses in endodontic procedures, such as root end and perforation fills and for apical closure in the apexification procedure. Calcium silicate hydrates (CSH), xCa(OH)2 ySiO2zH2O, of varying Ca/Si/H2O ratios are among the products formed in MTA.
Defined broadly, the term “nanostructured” is used to describe materials characterized by structural features of less than 100 nm in average size (WTEX Panel Report on Nanostructure Nanodevices, 1999). Clusters of small numbers of atoms or molecules in nanostructured materials often have properties (such as strength, electrical resistivity and conductivity, and optical absorption) that are significantly different from the properties of the same matter at the bulk scale. In the case of calcium phosphates and other bioactive inorganic materials, there are a number of reasons to believe that the combination of small particle size and high reactivity can lead to performance advantages in a range of clinical applications. For example, as set forth in the description of the preferred embedment hereinafter, experimental results showed that nano sized HA, when incorporated into a TTCP+DCPA calcium phosphate cement caused a drastic reduction in setting time from 30 min to 10-12 min. It is anticipated that nano particles of other calcium phosphate phases, which are ingredients of the various calcium phosphate cements in clinical use, will also significantly improve the setting and other handling properties, e.g., cohesiveness, injectability, etc., of the cements.
The apatite crystallites in human bone, enamel, dentin and cementum are all extremely small in size and can be considered as nanostructured materials. Because HA is the prototype for bioapatites, which are in nano crystalline forms, extensive efforts have been made to produce synthetic nano HA materials. Methods that have been used for preparing nano HA material include chemical precipitation, in some cases followed by spray drying or hydrothermal treatment, sol-gel approach, microemulsion techniques, precipitation from complex solution followed by microwave heating, wet chemical methods incorporating a freeze drying step, mechanochemical synthesis, and eletrodeposition. Additional studies reported synthesis of composites of nano HA and bioactive organic components including HA-collagen, HA-chondroitin sulfate or HA-chitosan using direct precipitation method, nano HA-polyamide using HA slurry and solution method, and Ca-deficient nano HA-high molecular weight poly (D,L-lactide) through a solvent-cast technique.
Preparation of microcrystalline and nanocrystalline HA have also been disclosed in the patent literature. U.S. Pat. No. 5,034,352 discloses that Spray drying is the preferred technique for converting the gelatinous precipitate of hydroxyapatite into the fine dry articles suitable for use in the agglomeration process. U.S. Pat. No. 4,897,250 discloses that calcium phosphate, including hydroxyapatite, precipitated by the reaction can be withdrawn in a powder form by any conventional techniques such as filtration, centrigual separation, and spray drying. U.S. Pat. No. 6,033,780 discloses a manufacturing method of a spherical apatite by means of a slurry comprising hydroxyapatite as its main component which is dried and powdered to prepare aggregates of primary apatite particles, preferably, spray dried to form spherical particles. U.S. Pat. No. 6,558,512 discloses that one method for preparing dense, rounded or substantially spherical ceramic particles such as calcium hydroxyapatite is by spray drying a slurry of about 20 to 40 weight % submicron particle size calcium hydroxyapatite. U.S. Pat. No. 6,592,989 provides a method of synthesizing hydroxyapatite comprising the steps of preparing a mixed material slurry by dispersing calcium hydroxide powder into a phosphoric acid solution and conducting a mechanochemical milling treatment. U.S. Pat. No. 5,585,318 provides methods for producing non-porous controlled morphology hydroxyapatite granules of less than 8 μm by a spray-drying process. Solid or hollow spheres or doughnut shapes can be formed by controlling the volume fraction and viscosity of the slurry as well as the spray-drying conditions. Finally, U.S. Pat. No. 6,013,591 discloses a method for preparing nanocrystalline HA that involves precipitating-a particulate apatite from solution having a crystallite size of less than 250 nm and a BET surface area of at least 40 m2/g. In all of the prior art methods cited above, HA was precipitated from a solution. The slurry or emulsion containing the precipitated HA was spray-dried to produce fine particles.
In the above methods described in the scientific or patent literature, the nano HA materials are formed in a solution environment, and in most cases, the product is washed with water or other solvents to remove impurity or undesired components. Exposure of the nano particles to additional solution environments is likely to result in significant interactions between the particle surfaces and the solvent, leading to modifications of the surface properties and a reduction in the high reactivity innate to the nano particles. Thus, there has persisted the need to identify methods and apparatus for the manufacture of high purity, amorphous or nearly amorphous nano particles, especially those comprised of Ca and P.